HOW TO BUILD A SUPERHERO

The Hulk had gamma radiation, Peter Parker had a radioactive spider, and the Spartans had the official 300 Workout (and CGI). What “double-muscled” mice have is a mutation in myostatin…Expressed primarily in skeletal muscle, myostatin is a secreted protein that modulates the proliferation and differentiation of muscle precursor cells, ultimately acting as a negative regulator of muscle growth.1 Mice without myostatin have uncontrolled muscle growth, which results in 2-3x more muscle mass!2 Since myostatin also regulates adipose tissue and metabolism, these myostatin knockout mice also have reduced body fat, and are resistant to fat accumulation.1

No, he isn’t just well-fed … this doubled-muscled mouse (right) is much larger than wildtype (left) because of a myostatin mutation! [Image: Lee Se-Jin.]

In the case of dogs, a mutation in myostatin not only enhances muscle growth, but also significantly affects racing performance.2Whippets (called “bully whippets” when they have this muscular phenotype) are significantly faster if they’re deficient in myostatin.2 Similarly, racing performance in horses has also been linked to a specific gene variant of myostatin.3

Whippets that are heterozygous for the myostatin mutation (middle) are more muscular than wildtype (left), and homozygous super-whippets (right) are even more heavily muscled! [Image: Mosher et al. (2007)]

In the agricultural industry, cattle with myostatin mutations have been of enormous interest, given that these animals convert food more efficiently into muscle.4 However, this increased meat yield is offset by other (expensive) problems; these Belgian Blue and Piedmontese breeds might have less bone, less fat, and 20% more muscle than regular cattle, but they also have decreased fertility rates and fewer viable calves.4

There’s even been a case of myostatin mutation in a human child, causing extreme muscle growth. At birth, this newborn boy already had “protruding muscles” in the thighs and upper arms, and by 4½ years, could suspend two 3-kg dumbbells horizontally, with his arms extended!5 While this child carries a homozygous myostatin mutation, his mother is heterozygous for the same mutation—and she’s a former pro athlete.5 Unfortunately, loss of myostatin could have negative side-effects (including decreased muscle oxidative capacity),6 so doctors will continue to monitor the child for potential health risks.

Despite what some shady internet ads claim, we still know very little about how myostatin inhibitors affect the body. Bodybuilders might see this as a recipe for instant muscles (or perhaps, the start of a really boring superhero origin story?), but researchers are investigating this as a possible therapy for muscle loss. Muscle wasting can occur during cancer, or in rarer diseases like Duchenne muscular dystrophy, and nearly everyone will experience age-related muscle loss; myostatin might be a good clinical target for any of these conditions. Indeed, the first clinical trial using myostatin inhibitors in humans was recently completed! As a Phase I clinical trial, this study is limited by its short duration and small sample size, but even so, has some promising results. When treated with myostatin inhibitors, subjects experienced a small (but significant) increase in lean body mass and decrease in fat mass—in just 29 days!1 Of course, this has to be repeated at a larger scale, and is only in early stages now, but this progress is encouraging. The potential for treating such a variety of conditions and patients is already, quite heroic.